Enteroviruses have long been suspected as potential etiologic agents of chronic muscle disease. Although they are not known to cause persistent infections, persistent enterovirus RNA has been detected in some patients. Experimental models have shown that enteroviral RNA assumes a double-stranded conformation (dsRNA) as part of its mechanism for persistence in muscle. However, the global effect of low levels of viral dsRNA in a long-lived tissue like skeletal muscle is unknown. This proposal is part of a long-range goal to understand the role of infectious agents in the pathogenesis of chronic muscle diseases such as chronic fatigue syndrome and the idiopathic inflammatory myopathies. The central hypothesis of this application is that low-level persistence of viral dsRNA is pathogenic for muscle. This hypothesis was formulated based on evidence from a mouse model that links coxsackievirus B1 (CVB1) RNA persistence to the development of chronic inflammatory myopathy. The rationale for the proposed research is that a lack of knowledge regarding the type of pathology caused by persistent enterovirus dsRNA has hampered investigations into the etiology and pathogenesis of these diseases. The central hypothesis will be tested through the pursuit of the following two specific aims: (1) establish a transgenic model to achieve regulated expression of CVB1 dsRNA in muscle and characterize the clinical disease associated with its expression, and (2) identify the diagnostic signature of muscle pathology mediated by viral dsRNA. The proposed work is innovative because it represents a novel way of viewing chronic disease caused by enteroviruses-namely, that it is the persistent dsRNA itself and not solely the acute infection that mediates pathology. The outcome of these studies is expected to lead to the identification of a diagnostic signature for chronic muscle diseases caused by persistent viral dsRNA. The results will advance the development of better tools for the epidemiologic study, diagnosis, and treatment of diseases where enterovirus infection has been implicated.